THBD

Summary

THBD (thrombomodulin, HGNC:11784) is a protein-coding gene on chromosome 20p11.21, encoding Thrombomodulin (P07204). Endothelial cell receptor that plays a critical role in regulating several physiological processes including hemostasis, coagulation, fibrinolysis, inflammation, and angiogenesis.

The protein encoded by this intronless gene is an endothelial-specific type I membrane receptor that binds thrombin. This binding results in the activation of protein C, which degrades clotting factors Va and VIIIa and reduces the amount of thrombin generated. Mutations in this gene are a cause of thromboembolic disease, also known as inherited thrombophilia.

Source: NCBI Gene 7056 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombomodulin-related bleeding disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 702 total — 1 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_000361

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11784
Approved symbol	THBD
Name	thrombomodulin
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Aliases	CD141, THRM, BDCA-3
Ensembl gene	ENSG00000178726
Ensembl biotype	protein_coding
OMIM	188040
Entrez	7056

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000377103

RefSeq mRNA: 1 — MANE Select: NM_000361 NM_000361

CCDS: CCDS13148

Canonical transcript exons

ENST00000377103 — 1 exons

Exon	Start	End
ENSE00001472793	23045633	23049672

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 96.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3499 / max 479.2819, expressed in 1274 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186660	13.5442	1249
209018	0.5771	370
186653	0.2286	76

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	96.20	gold quality
gingiva	UBERON:0001828	95.67	gold quality
vena cava	UBERON:0004087	94.98	gold quality
right lung	UBERON:0002167	94.75	gold quality
skin of hip	UBERON:0001554	94.18	gold quality
skin of abdomen	UBERON:0001416	94.05	gold quality
upper leg skin	UBERON:0004262	93.91	gold quality
periodontal ligament	UBERON:0008266	93.35	gold quality
skin of leg	UBERON:0001511	93.29	gold quality
lower lobe of lung	UBERON:0008949	93.27	gold quality
upper lobe of left lung	UBERON:0008952	93.25	gold quality
zone of skin	UBERON:0000014	93.09	gold quality
left coronary artery	UBERON:0001626	92.88	gold quality
left uterine tube	UBERON:0001303	92.83	gold quality
lung	UBERON:0002048	92.81	gold quality
upper lobe of lung	UBERON:0008948	92.75	gold quality
coronary artery	UBERON:0001621	92.43	gold quality
ascending aorta	UBERON:0001496	91.99	gold quality
thoracic aorta	UBERON:0001515	91.85	gold quality
cervix squamous epithelium	UBERON:0006922	91.78	gold quality
descending thoracic aorta	UBERON:0002345	91.18	gold quality
right coronary artery	UBERON:0001625	91.16	gold quality
right lobe of thyroid gland	UBERON:0001119	91.08	gold quality
omental fat pad	UBERON:0010414	90.75	gold quality
peritoneum	UBERON:0002358	90.70	gold quality
superficial temporal artery	UBERON:0001614	90.54	gold quality
mammalian vulva	UBERON:0000997	90.17	gold quality
squamous epithelium	UBERON:0006914	90.14	gold quality
left lobe of thyroid gland	UBERON:0001120	89.92	gold quality
aorta	UBERON:0000947	89.91	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	291.21
E-CURD-11	yes	217.80
E-GEOD-135922	yes	35.63
E-GEOD-134144	yes	32.57
E-HCAD-1	yes	17.19
E-MTAB-9543	yes	11.25
E-MTAB-10553	yes	7.35
E-GEOD-130148	yes	4.53
E-MTAB-10137	no	4.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, EP300, FOSL1, GLI2, KLF2, KLF4, NFKB1, PARP1, RARA, RARB, RARG, RELA, RXRA, SP1, TP53, TXK

miRNA regulators (miRDB)

106 targeting THBD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• a tumor marker for cardiac myxoma (PMID:11642722)
• association between decreased pulmonary endothelial cell thrombomodulin and local fibrin deposition in pneumonia (PMID:11734675)
• Establishment of a standard assay method for human thrombomodulin and determination of the activity of the Japanese reference standard (PMID:11846431)
• Smoking carriers of the THRM -33G/A polymorphism had a nearly 10-fold increased risk of young AMI compared with nonsmoking non-carriers. The prothrombotic milieu due to decreased THRM expression in this polymorphism may be an important mechanism of AMI. (PMID:11848462)
• Pts with low soluble thrombomodulin levels had a significantly increased risk of hemorrhagic but not ischemic stroke. (PMID:11858479)
• vWF and tPAag but not thrombomodulin in the present population are independent markers of atherosclerosis. (PMID:11864703)
• Arsenite caused a decrease of t-PA mRNA level and a rise of both PAI-1 mRNA level and activity in microvascular endothelial cells, but not umbilical vein endothelial cells, suggesting a role in Blackfoot disease, a peripheral vascular occlusive disease. (PMID:11864708)
• Naturally occurring mutations in the thrombomodulin gene result in impaired function (PMID:11986219)
• substantial reduction of vascular endothelial thrombomodulin expression throughout human diabetic neuropathy may contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy (PMID:12031986)
• functional epitope of thrombin recognizing thrombomodulin was mapped using Ala-scanning mutagenesis of 54 residues located around the active site, the Na(+) binding loop, the 186-loop, the autolysis loop, exosite I, and exosite II (PMID:12068020)
• Thrombomodulin gene mutation of the 5’-regulatory region might constitute risks for arterial and venous thromboses. (PMID:12204814)
• Reduced thrombomodulin in human peripheral nerve microvasculature (PMID:12210386)
• thrombomodulin-dependent activation of protein C is regulated by Smad6 and Smad7 (PMID:12407115)
• results suggest that oxidized phospholipids inhibit transcription of the thrombomodulin gene in vascular endothelium by inhibiting the binding of retinoic acid receptor beta-retinoid x receptor alpha heterodimer and Sp1 and Sp3 to thrombomodulin promoter (PMID:12576329)
• Results show that VR1 is a subsite of exosite 1 on thrombin’s surface, which regulates exclusive binding of either plasminogen activator inhibitor 1 or thrombomodulin. (PMID:12709053)
• The increase of thrombomodulin secretion results in homeostatic disturbance, which might be one of the important mechanims of multiple organs dysfunction syndrome. (PMID:12831611)
• thrombomodulin level may be a molecular marker of the latent progression of atherosclerosis in hypertensive patients (PMID:12862205)
• Behcet’s disease with vascular complications involves higher levels of thrombomodulin. (PMID:12918732)
• the Stx2-induced decrease of TM expression in glomerular endothelial cells might contribute to the local procoagulant state present in hemolytic uremic syndrome (PMID:12920633)
• TM can function as a Ca2+-dependent cell-to-cell adhesion molecule. Binding of specific carbohydrates to the lectin-like domain is essential for this specific function (PMID:12951323)
• An interdomain connection modulated by the methionine linker residue at position 388 between the fourth and fifth domains of thrombomodulin is critical for thrombin-binding and anticoagulant cofactor activity. (PMID:14556624)
• posttranscriptional downregulation of TM mRNA by IFN-gamma that identifies the 3’-UTR as a target of IFN-gamma-stimulated destabilization (PMID:14769148)
• variation in the promoter region of thrombomodulin (V/delTT) is associated with an elevated risk for myocardial infarct in Northern but not in Southern Europeans (PMID:14983241)
• Role of thrombomodul in the pathogenesis of coagulopathy or thrombosis in cyanotic congenital heart disease (PMID:14987915)
• Thrombomodulin may not play an important inflammation-related role in plaque development. (PMID:15080580)
• TM was found on the surace of islet cells as well as vascular endothelial cells, whereas no TM was found in the components of exocrine pancreas (PMID:15099291)
• Review. TM, APC, & EPCR impact coagulation, inflammation, fibrinolysis, & cell proliferation. We review the functions of this complex multimolecular system & how its components maintain homeostasis under hypercoagulable &/or proinflammatory conditions. (PMID:15178554)
• identified 10 point mutations and 2 small deletions in the promoter region in 182 patients with acute coronary syndrome (PMID:15183044)
• Among women aged 15 to 44 years, the A Allele genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke (PMID:15574195)
• mechanism of thrombomodulin action is to kinetically facilitate the productive encounter of thrombin and protein C and to allosterically change the conformation of the activation peptide of protein C for optimal presentation to the thrombin active site (PMID:15582990)
• The profibrinolytic effect of plasma TM may contribute to the bleeding tendency observed in some factor XI -deficient patients (PMID:15613027)
• mechanism involving competition by NF-kappaB for limited pools of the transcriptional coactivator p300 necessary for TM gene expression (PMID:15677570)
• PC interactions with thrombin and thrombomodulin are likely contribute in a secondary or minor way to protein substrate affinity (PMID:15705565)
• Lack of thrombomodulin expression due to methylation of the promoter CpG island is associated with malignant melanoma (PMID:15714116)
• Thrombomodulin gene polymorphisms do not have a role in venous thromboembolism (PMID:15842356)
• Elevation of adiponectin may be a defense mechanism against endothelial damage, reflected by elevated CD146 and thrombomodulin. (PMID:15897668)
• Statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease. (PMID:16043642)
• thrombomodulin induces Ca2+ signals and nitric oxide synthesis through EGFR and calmodulin kinase II (PMID:16126727)
• Thrombomodulin (TM) expression in the stem villous vasculature and syncytiotrophoblast of the placenta is impaired in severe preeclampsia (PMID:16136486)
• CRP significantly decreases the expression of TM and EPCR in human endothelial cells, thereby promoting thrombogenic conditions. (PMID:16153429)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Thbd	ENSMUSG00000074743
rattus_norvegicus	Thbd	ENSRNOG00000004687
drosophila_melanogaster	knk	FBGN0001321
drosophila_melanogaster	CG34355	FBGN0085384
caenorhabditis_elegans		WBGENE00020921

Protein

Protein identifiers

Thrombomodulin — P07204 (reviewed: P07204)

Alternative names: Fetomodulin

All UniProt accessions (1): P07204

UniProt curated annotations — full annotation on UniProt →

Function. Endothelial cell receptor that plays a critical role in regulating several physiological processes including hemostasis, coagulation, fibrinolysis, inflammation, and angiogenesis. Acts as a cofactor for thrombin activation of protein C/PROC on the surface of vascular endothelial cells leading to initiation of the activated protein C anticoagulant pathway. Also accelerates the activation of the plasma carboxypeptidase B2/CPB2, which catalyzes removal of C-terminal basic amino acids from its substrates including kinins or anaphylatoxins leading to fibrinolysis inhibition. Plays critical protective roles in changing the cleavage specificity of protease-activated receptor 1/PAR1, inhibiting endothelial cell permeability and inflammation. Suppresses inflammation distinctly from its anticoagulant cofactor activity by sequestering HMGB1 thereby preventing it from engaging cellular receptors such as RAGE and contributing to the inflammatory response.

Subunit / interactions. Interacts with ITGAL, ITGAM and ITGB2. Interacts with thrombin/F2; this interaction switches the specificity of thrombin from a procoagulant to an anticoagulant and antifibrinolytic protease. Interacts with ANGP1 and ANGP2; these interactions significantly inhibit the generation of activated PC and TAFIa/CPB2 by the thrombin/thrombomodulin complex. Interacts with PF4; this interaction enhances generation of activated protein C. Interacts with HMGB1; this interaction inhibits HMGB1 inflammatory activity.

Subcellular location. Membrane.

Tissue specificity. Endothelial cells are unique in synthesizing thrombomodulin.

Post-translational modifications. N-glycosylated. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Disease relevance. Thrombophilia due to thrombomodulin defect (THPH12) [MIM:614486] A hemostatic disorder characterized by a tendency to thrombosis. The disease may be caused by variants affecting the gene represented in this entry. The role of thrombomodulin in thrombosis is controversial. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. Hemolytic uremic syndrome, atypical, 6 (AHUS6) [MIM:612926] An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.

Domain organisation. Extracellular region (481-515) contains a binding side for alpha-L/beta-2 and alpha-M/beta-2 integrin.

RefSeq proteins (1): NP_000352* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001304	C-type_lectin-like	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR015149	Tme5_EGF-like	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026823	cEGF	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR052126	Spindle_Org/Thrombomodulin	Family
IPR057350	THBD	Domain

Pfam: PF00059, PF07645, PF09064, PF12662, PF14670, PF25444

UniProt features (83 total): strand 22, disulfide bond 19, sequence variant 11, domain 7, glycosylation site 7, helix 5, region of interest 2, topological domain 2, mutagenesis site 2, turn 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
1DX5	X-RAY DIFFRACTION	2.3
5TO3	X-RAY DIFFRACTION	2.34
3GIS	X-RAY DIFFRACTION	2.4
1HLT	X-RAY DIFFRACTION	3
7T4R	ELECTRON MICROSCOPY	3.3
1ADX	SOLUTION NMR
1DQB	SOLUTION NMR
1EGT	SOLUTION NMR
1FGD	SOLUTION NMR
1FGE	SOLUTION NMR
1TMR	SOLUTION NMR
1ZAQ	SOLUTION NMR
2ADX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07204-F1	79.35	0.42

Antibody-complex structures (SAbDab): 1 — 7T4R

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 342

Disulfide bonds (19): 137–158, 245–256, 252–265, 267–280, 288–296, 292–308, 310–323, 329–340, 336–349, 351–362, 369–378, 374–388, 390–404, 408–413, 417–425, 427–439, 445–455, 451–464, 466–480

Glycosylation sites (7): 47, 115, 116, 382, 409, 490, 492

Mutagenesis-validated functional residues (2):

Position	Phenotype
490	improved overall glycosaminoglycan attachment, likely due to improved xylosyltransferase acceptor consensus sequence aro
492	reduced glycosaminoglycan attachment.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-9769739	Regulation of clotting cascade
R-HSA-140875

MSigDB gene sets: 361 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_PROTEIN_ACTIVATION_CASCADE, WALLACE_PROSTATE_CANCER_RACE_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_WOUND_HEALING, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOBP_REGULATION_OF_COAGULATION, JAEGER_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_PLATELET_ACTIVATION, GOBP_PLATELET_ACTIVATION, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_COAGULATION

GO Biological Process (13): proteolysis (GO:0006508), female pregnancy (GO:0007565), blood coagulation (GO:0007596), response to X-ray (GO:0010165), negative regulation of platelet activation (GO:0010544), negative regulation of blood coagulation (GO:0030195), zymogen activation (GO:0031638), response to lipopolysaccharide (GO:0032496), response to cAMP (GO:0051591), negative regulation of fibrinolysis (GO:0051918), blood coagulation, common pathway (GO:0072377), hemostasis (GO:0007599), negative regulation of coagulation (GO:0050819)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), calcium ion binding (GO:0005509), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), vacuolar membrane (GO:0005774), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), apicolateral plasma membrane (GO:0016327), serine-type endopeptidase complex (GO:1905370), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Hemostasis	1
Coagulation pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
coagulation	2
response to oxygen-containing compound	2
cellular anatomical structure	2
protein metabolic process	1
multi-organism reproductive process	1
multi-multicellular organism process	1
hemostasis	1
wound healing	1
response to ionizing radiation	1
regulation of platelet activation	1
platelet activation	1
negative regulation of blood coagulation	1
negative regulation of cell activation	1
blood coagulation	1
regulation of blood coagulation	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
protein processing	1
response to molecule of bacterial origin	1
response to lipid	1
response to purine-containing compound	1
response to organophosphorus	1
positive regulation of blood coagulation	1
positive regulation of response to external stimulus	1
fibrinolysis	1
negative regulation of biological process	1
regulation of fibrinolysis	1
protein activation cascade	1
blood coagulation, fibrin clot formation	1
regulation of body fluid levels	1
regulation of coagulation	1
negative regulation of multicellular organismal process	1
signaling receptor activity	1
metal ion binding	1
molecular transducer activity	1
binding	1
vacuole	1
bounding membrane of organelle	1
membrane	1

Protein interactions and networks

STRING

2624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THBD	PROCR	Q9UNN8	998
THBD	F2R	P25116	965
THBD	TFPI	P10646	963
THBD	F3	P13726	963
THBD	CPB2	Q96IY4	958
THBD	F2	P00734	928
THBD	PROC	P04070	923
THBD	SERPINC1	P01008	913
THBD	PLAT	P00750	904
THBD	VWF	P04275	899
THBD	CLEC4C	Q8WTT0	898
THBD	PLG	P00747	890
THBD	CD1C	P29017	890
THBD	CLEC9A	Q6UXN8	888
THBD	F7	P08709	873

IntAct

80 interactions, top by confidence:

A	B	Type	Score
THBD	TMX2	psi-mi:“MI:0915”(physical association)	0.560
THBD	KIR2DL3	psi-mi:“MI:0915”(physical association)	0.560
THBD	PHF24	psi-mi:“MI:0915”(physical association)	0.560
THBD	RHBDD2	psi-mi:“MI:0915”(physical association)	0.560
THBD	AQP6	psi-mi:“MI:0915”(physical association)	0.560
THBD	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
THBD	CD79A	psi-mi:“MI:0915”(physical association)	0.560
THBD	EBP	psi-mi:“MI:0915”(physical association)	0.560
THBD	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
THBD	CYBC1	psi-mi:“MI:0915”(physical association)	0.560
THBD	GPX8	psi-mi:“MI:0915”(physical association)	0.560
THBD	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
THBD	AIG1	psi-mi:“MI:0915”(physical association)	0.560
THBD	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
THBD	MUC1	psi-mi:“MI:0915”(physical association)	0.560
THBD	APOC4	psi-mi:“MI:0915”(physical association)	0.560
THBD	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
THBD	MMGT1	psi-mi:“MI:0915”(physical association)	0.560
THBD	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
THBD	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
THBD	SLC35C2	psi-mi:“MI:0915”(physical association)	0.560
	THBD	psi-mi:“MI:0915”(physical association)	0.560
THBD	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
THBD	PDZK1IP1	psi-mi:“MI:0915”(physical association)	0.560
THBD	F2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (42): THBD (Synthetic Growth Defect), THBD (Two-hybrid), THBD (Proximity Label-MS), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid), THBD (Two-hybrid)

ESM2 similar proteins: A1A5Y0, A2ASQ1, O00468, O00548, O57409, O89103, O95428, P06579, P07204, P0C5J5, P15306, P20063, P25304, P31696, P97607, P97677, P98160, Q05793, Q08E66, Q14112, Q2PC93, Q501P1, Q53RD9, Q5W7P8, Q61483, Q61810, Q66PY1, Q6NUX0, Q6NZL8, Q6ZRI0, Q71U07, Q75N90, Q7T3Q2, Q8IWY4, Q8IX30, Q8JZM4, Q8NFT8, Q8R0S6, Q8R4Y4, Q8VIK5

Diamond homologs: A8WGB1, B3EWY9, B5DFC9, E1BMV3, G3V928, O19045, O43897, O57382, O73775, O75095, O88322, O88947, P00743, P07204, P07225, P10493, P13497, P14543, P15306, P21941, P23142, P25155, P25723, P35951, P37889, P48960, P51942, P53813, P98063, P98069, P98070, P98095, P98118, P98157, P98163, Q07954, Q08761, Q08879, Q09165, Q14112

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CBP/p300	“up-regulates quantity by expression”	THBD	“transcriptional regulation”
NfKb-p65/p50	“down-regulates quantity by repression”	THBD	“transcriptional regulation”
KLF2	“up-regulates quantity by expression”	THBD	“transcriptional regulation”
KLF4	“up-regulates activity”	THBD	“transcriptional regulation”
NFKB1	“down-regulates quantity by repression”	THBD	“transcriptional regulation”
PARP1	“up-regulates quantity by expression”	THBD	“transcriptional regulation”
PARP1	“down-regulates quantity by repression”	THBD	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	THBD	“transcriptional regulation”
“all-trans-retinoic acid”	“up-regulates quantity by expression”	THBD
THBD	“form complex”	Thrombin-Thrombomodulin	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

702 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	7
Uncertain significance	507
Likely benign	111
Benign	27

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
12715	NM_000361.3(THBD):c.142G>A (p.Ala48Thr)	Pathogenic
3383410	NM_000361.3(THBD):c.1392C>A (p.Cys464Ter)	Likely pathogenic
3587112	NM_000361.3(THBD):c.1360del (p.Val454fs)	Likely pathogenic
3587124	NM_000361.3(THBD):c.920C>A (p.Ser307Ter)	Likely pathogenic
3587142	NM_000361.3(THBD):c.127del (p.Ala43fs)	Likely pathogenic
3893285	NM_000361.3(THBD):c.1440_1441del (p.Cys480_Asp481delinsTer)	Likely pathogenic
627170	NM_000361.3(THBD):c.1487del (p.Pro496fs)	Likely pathogenic
627252	NM_000361.3(THBD):c.1611C>A (p.Cys537Ter)	Likely pathogenic

SpliceAI

11 predictions. Top by Δscore:

Variant	Effect	Δscore
20:23046810:C:CC	acceptor_gain	0.4700
20:23046808:CA:C	acceptor_gain	0.4600
20:23046781:C:CG	acceptor_gain	0.4000
20:23046809:A:AC	acceptor_gain	0.3700
20:23046805:CAACA:C	acceptor_gain	0.2900
20:23049631:T:TA	donor_gain	0.2900
20:23046823:GTAAT:G	acceptor_gain	0.2700
20:23046826:ATAAT:A	acceptor_gain	0.2500
20:23046783:A:C	acceptor_gain	0.2200
20:23046782:T:C	acceptor_gain	0.2100
20:23046802:T:TC	acceptor_gain	0.2100

AlphaMissense

3745 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:23048776:C:A	W243C	0.999
20:23048776:C:G	W243C	0.999
20:23048800:C:A	W235C	0.999
20:23048800:C:G	W235C	0.999
20:23049046:C:A	W153C	0.999
20:23049046:C:G	W153C	0.999
20:23049139:C:A	W122C	0.999
20:23049139:C:G	W122C	0.999
20:23049175:C:A	W110C	0.999
20:23049175:C:G	W110C	0.999
20:23049244:C:A	W87C	0.998
20:23049244:C:G	W87C	0.998
20:23048189:C:G	C439S	0.996
20:23048190:A:T	C439S	0.996
20:23048294:C:G	C404S	0.996
20:23048295:A:T	C404S	0.996
20:23049350:C:T	C52Y	0.996
20:23048323:G:C	F394L	0.995
20:23048323:G:T	F394L	0.995
20:23048325:A:G	F394L	0.995
20:23048464:G:C	F347L	0.995
20:23048464:G:T	F347L	0.995
20:23048466:A:G	F347L	0.995
20:23048537:C:G	C323S	0.995
20:23048538:A:T	C323S	0.995
20:23049371:A:C	F45C	0.995
20:23048324:A:C	F394C	0.994
20:23048465:A:C	F347C	0.994
20:23048486:C:G	C340S	0.994
20:23048487:A:T	C340S	0.994

dbSNP variants (sampled 300 via entrez): RS1000711528 (20:23047733 G>A), RS1000740139 (20:23047107 G>A), RS1001935035 (20:23046419 C>G), RS1002114154 (20:23046035 T>C,G), RS1002281942 (20:23051542 G>A), RS1002411640 (20:23045511 T>A,C), RS1002638698 (20:23050206 G>A), RS1002709786 (20:23051312 G>C), RS1002810292 (20:23050729 C>T), RS1003818570 (20:23049671 A>G), RS1004255849 (20:23045646 A>G,T), RS1004783443 (20:23048170 G>C,T), RS1005092424 (20:23050566 C>T), RS1006474361 (20:23051384 G>A), RS1006566595 (20:23045139 T>C)

Disease associations

OMIM: gene MIM:188040 | disease phenotypes: MIM:612926, MIM:614486

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombomodulin-related bleeding disorder	Strong	Autosomal dominant
atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
thrombomodulin-related bleeding disorder	Moderate	AD
thrombomodulin-related bleeding disorder	Limited	AR
atypical hemolytic-uremic syndrome	Disputed	AD

Mondo (5): atypical hemolytic-uremic syndrome with thrombomodulin anomaly (MONDO:0013044), thrombomodulin-related bleeding disorder (MONDO:0013775), kidney disorder (MONDO:0005240), atypical hemolytic-uremic syndrome (MONDO:0016244), thrombocytopenia (MONDO:0002049)

Orphanet (3): Thrombomodulin-related bleeding disorder (Orphanet:436169), Atypical hemolytic uremic syndrome (Orphanet:2134), OBSOLETE: Atypical hemolytic uremic syndrome with thrombomodulin anomaly (Orphanet:217023)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001919	Acute kidney injury
HP:0001937	Microangiopathic hemolytic anemia
HP:0002204	Pulmonary embolism
HP:0002625	Deep venous thrombosis
HP:0003138	Increased blood urea nitrogen
HP:0003259	Elevated circulating creatinine concentration
HP:0003581	Adult onset
HP:0005421	Decreased circulating complement C3 concentration
HP:0005575	Hemolytic-uremic syndrome
HP:0100519	Anuria
HP:0100724	Hypercoagulability

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002279_6	PR interval in Tripanosoma cruzi seropositivity	2.000000e-07
GCST003377_2	Venous thromboembolism	2.000000e-08
GCST003377_4	Venous thromboembolism	5.000000e-08
GCST009731_56	Blood protein levels in cardiovascular risk	6.000000e-46
GCST011796_7	Lung function (FVC) in asthma	7.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0007774	thrombomodulin measurement
EFO:0004312	vital capacity

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C566057	Thrombophilia due to Thrombomodulin Defect (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1042580	Toxicity	3	warfarin

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1042580	THBD	3	2.50	1	warfarin
rs3176123	THBD		0.00	0

CTD chemical–gene interactions

98 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	6
Estradiol	decreases expression, increases expression, affects cotreatment	5
Tretinoin	decreases reaction, increases expression, decreases expression	5
Progesterone	affects cotreatment, decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression, decreases reaction, affects cotreatment, increases expression	4
Simvastatin	decreases reaction, increases expression	4
sodium arsenite	affects cotreatment, affects expression, decreases expression	3
Arsenic Trioxide	decreases expression, affects expression, decreases reaction, increases expression	3
Air Pollutants	increases expression, increases abundance	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Doxorubicin	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
arsenite	decreases expression, increases methylation	2
Vehicle Emissions	decreases expression, increases expression	2
Formaldehyde	decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	increases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8QU	Abcam HCT 116 THBD KO	Cancer cell line	Male
CVCL_B9T8	Abcam A-549 THBD KO	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes